Administration route-commended concise organ-selective mRNA transfection (ACCOST) by cyclic disulfide-primed short polyethylenimine

mRNA technology holds great promise for addressing a spectrum of diseases. Achieving widespread clinical utility of mRNA therapeutics requires effective transfection of mRNA to specific organs. Here we introduce a cyclic disulfide-primed short polyethyleneimine (CD-PEI) polymer that demonstrates administration route-commended concise organ-selective mRNA transfection (ACCOST) in vivo. The cyclic disulfide groups on the PEI polymer facilitate thiol-mediated cytosolic mRNA delivery and high transfection of different types of cells including hard-to-transfect immune cells. Remarkably, CD-PEI-mRNA complex achieves nearly 100 % organ-specific transfection in pancreas, lymph nodes, brain/spinal cord, and spleen via intraperitoneal, subcutaneous, intrathecal injection, and intravenous injections, respectively, with negligible accumulation in non-target organs. The intravenous injection to pregnant mice results in selective mRNA expression in the placenta instead. The spleen targeting occurs likely via erythrocyte-hijacking mechanism and systemically administered mRNA vaccines elicit robust antigen-specific anti-tumor immunity in murine B16-OVA model. Therefore, our ACCOST technology presents a novel strategy for organ-specific mRNA transfection.